Abstract
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases, which play a pivotal role in invasion, migration, and angiogenesis of glioma. Therefore, controlling MMPs is potentially an important therapeutic strategy for glioma. In the present study, we found that exogenous cell-permeable short-chain C2 ceramide inhibits phorbol myristate acetate (PMA)-induced MMP-1, -3, and -9 gene expressions in U87MG and U373MG human astroglioma cells. In addition, C2 ceramide inhibited the protein secretion and enzymatic activities of MMP-1, -3, and -9. The Matrigel invasion assay and wound healing assay showed that C2 ceramide suppresses the in vitro invasion and migration of glioma cells, which appears to be involved in strong inhibition of MMPs by C2 ceramide. Subsequent mechanistic studies revealed that C2 ceramide inhibits PMA-induced mitogen-activated protein kinase (MAPK) phosphorylation and nuclear factor (NF)-κB/activator protein (AP)-1 DNA binding activities. Furthermore, C2 ceramide significantly inhibited PMA-induced reactive oxygen species (ROS) production and NADPH oxidase 4 (NOX4) expression, and inhibition of ROS by diphenylene iodonium (DPI, NADPH oxidase inhibitor) mimicked the effects of C2 ceramide on MMP expression and NF-κB/AP-1 via inhibition of p38 MAPK. The results suggest C2 ceramide inhibits MMP expression and glioma invasion, at least partly, by modulating ROS-p38 MAPK signaling axis and other MAPK signaling pathways.
Highlights
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases able to degrade or remodel extracellular matrix (ECM) proteins in various physiological and pathological conditions [1,2]
We discovered that C2 ceramide strongly inhibits the expression and enzymatic activities of MMP-1, -3, and -9 induced by phorbol myristate acetate (PMA) in human astroglioma cells
We found that PMA (50 ng/mL), which is a strong tumor inducer, significantly enhanced MMP-1, -3, and -9 mRNA expressions, whereas pre-treatment with C2 ceramide resulted in an inhibition of the MMP-1, -3, and -9 expressions in both the U87MG and U373MG cells (Figure 1A–D)
Summary
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases able to degrade or remodel extracellular matrix (ECM) proteins in various physiological and pathological conditions [1,2]. Malignant gliomas are the most common primary brain tumors in adults, and are characterized by cell proliferation, angiogenesis, and insidious infiltration to the brain [4]. In human gliomas, increased MMP levels promote tumor-cell invasion by degrading the extracellular matrix (ECM) and tightening junction proteins [5]. MMP-3 plays a critical role in glioma invasiveness through degradation of hyaluronic acid-rich matrix of the brain [7]. The level of MMP-9 was found to be increased during the growth of glioblastoma cells intracerebrally implanted in nude mice [8]. Based on these findings, controlling MMP expression has been proposed as an important therapeutic target for malignant glioma treatments
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